Process for the preparation of deuterated ethanol from D2

ABSTRACT

The invention relates to a process for the preparation of a deuterated ethanol from an acetic acid, an acetate, or an amide by reaction with D2 in the presence of a transition metal catalyst.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of adeuterated ethanol from D₂.

BACKGROUND OF THE INVENTION

Deuterium (D or ²H) is a stable, non-radioactive isotope of hydrogen.Deuterium-enriched organic compounds such as a deuterated ethanol areknown. U.S. Pat. No. 8,658,236 describes an alcoholic beverage of waterand ethanol, wherein at least 5 mole percent of the ethanol is adeuterated ethanol. This alcoholic beverage is believed to diminish thenegative side effects associated with the consumption of ethanol.

The production of a deuterated-ethanol containing alcoholic beveragerequires the preparation of a deuterated ethanol in an efficient, safe,and cost-effective manner. A known process for the preparation of adeuterated alcohol (e.g., deuterated ethanol) involves an H/D exchangereaction between a non-deuterated alcohol and D₂O. Depending on theprocess, the resulting deuterated alcohol may comprise deuterium indifferent positions. Examples of such processes can be found inChemistry Letters 34, No. 2 (2005), p. 192-193 “Ruthenium catalyzeddeuterium labelling of α-carbon in primary alcohol and primary/secondaryamine in D₂O”; Adv. Synth. Catal. 2008, 350, p. 2215-2218 “A method forthe regioselective deuteration of alcohols”; Org. Lett. 2015, 17, p.4794-4797 “Ruthenium Catalyzed Selective α- and α,β-Deuteration ofAlcohols Using D₂O” and Catalysis Communications 84 (2016) p. 67-70“Efficient deuterium labelling of alcohols in deuterated water catalyzedby ruthenium pincer complexes”.

Other routes to produce a deuterated alcohol involve several consecutivereactions requiring expensive and/or hazardous material. For each ofthese transformations, purification and isolation of the intermediatesare necessary.

In view of the above, it is desirable to be able to synthesizedeuterated ethanol in an efficient, safe and cost-effective manner. Itis further desirable to synthesize deuterated ethanol with deuterationsubstantially only at a desired position(s).

SUMMARY OF THE INVENTION

In an aspect, the present invention provides a process for thepreparation of deuterated ethanol from ethanol, D₂, and a catalyst.

These and other aspects, which will become apparent during the followingdetailed, have achieved by the inventors' discovery of a new process ofmaking deuterated ethanol.

DETAILED DESCRIPTION OF THE INVENTION

Thus, in an aspect, the present invention provides a novel process forthe preparation of a deuterated ethanol of formula (I):CR¹R²R³CR⁴R⁵OD  (I)

comprising: reacting compound (II) with D₂ in the presence of a catalystof formulaML_(a)X_(b)  (III)wherein:

-   -   R¹-R⁵ are independently H or D, provided that the abundance of D        in R⁴ and R⁵ is at least 70%;    -   compound (II) is selected from: acetic acid, an acetate, and an        amide;    -   M is a transition metal;    -   L is a ligand;    -   X is a counterion;    -   a is an integer selected from 1-5; and,    -   b is an integer selected from 0-5.

The abundance of D in R⁴ and R⁵ (the CH₂ position) and in R¹, R², and R³(the CH₃ position) can be measured by ¹H NMR. The 70% abundance of D inR⁴ and R⁵ means that 70% of all R⁴ and R⁵ present are D (as opposed tothe natural abundance of 0.01%).

The process of the present invention uses D₂ as the deuterium sourcewhich is a non-toxic gas. The amount of the catalyst (III) required forthe process is very small, making the process cost effective. Also, thecatalyst (III) can be easily separated from the desired product.

In another aspect, the abundance of D in R⁴ and R⁵ is at least 80%.Additional examples of the abundance of D in R⁴ and R⁵ include at least90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 99.5%.

In another aspect, the incorporation of D occurs preferentially in R⁴and R⁵ over R¹-R³. In another aspect, the abundance of D in R¹-R³ is atmost 50%. Additional examples of the abundance of D in R¹-R³ include atmost 45, 40, 35, 30, 25, 20, 15, 10, 5, and 1%.

In another aspect, the abundance of D in R⁴ and R⁵ is at least 90% andthe abundance of D in R¹-R³ is at most 5%. Additional examples include(a) at least 95% and at most 1%, and (b) at least 99% and at most 1%.

The conversion of ethanol to deuterated ethanol in the present processcan be determined by ¹H NMR. The conversion is the molar ratio ofdeuterated ethanol formed divided by the initial amount of startingethanol (un-enriched ethanol). In an aspect, the conversion percentage(molar ratio×100) is at least 90%. Additional examples of the conversionpercentage include at least 95%, at least 98%, and at least 99%.

As noted above, compound (II) is selected from acetic acid, an acetate,and an amide.

In another aspect, compound (II) is acetic acid, which is a compoundhaving the formula CH₃COOH (or CH₃CO₂H).

In another aspect, compound (II) is an acetate of formula (IIA):CH₃COOR⁶  (IIA)wherein:

R⁶ is selected from: a C₁ or C₃₋₁₀ alkyl group, a C₁-C₁₀ substitutedalkyl group, a C₆₋₁₈ aromatic ring group, a C₆₋₁₈ substituted aromaticring group, and a glycol ether group;

alternatively, R⁶ is selected from: —R⁷—OCOCH₃

and —CH—(R⁸OCOCH₃)(R⁹OCOCH₃);

R⁷ is selected from: a C₁₋₁₀alkylene group, a substituted C₁₋₁₀ alkylenegroup, a C₆₋₁₈ aromatic ring group, a C₆₋₁₈ substituted aromatic ringgroup, and a glycol ether group; and,

R⁸ and R⁹ are independently selected from: a C₁₋₁₀ alkylene group, asubstituted C₁₋₁₀ alkylene group, a C₆₋₁₈ aromatic ring group, a C₆₋₁₈substituted aromatic ring group, and a glycol ether group.

In another aspect, in the acetate represented by the formula CH₃COOR⁶,R⁶ has a structure such that an alcohol made from R⁶ represented by R⁶OHis a primary or a secondary alcohol. In other words, R⁶ is bonded toCH₃COO— by a carbon atom having at least one H (e.g., a —CH—, CH₂—, or—CH₃ moiety).

Examples of the acetate represented by the formula CH₃CO₂R⁶ includemethyl acetate, n-propyl acetate, i-propyl acetate, n-butyl acetate,i-butyl acetate, di(propylene glycol) methyl ether acetate, and phenylacetate.

Examples of the acetate represented by the formula CH₃CO₂R⁷OCOCH₃include ethylene glycol diacetate (R⁷ is ethylene) and propylene glycoldiacetate (R⁷ is i-propylene).

An example of the acetate represented by the formulaCH₃CO₂CH(R⁸OCOCH₃)(R⁹OCOCH₃) is glyceryl triacetate (R⁸ and R⁹═CH₂).

In another aspect, compound (II) is an acetate selected from: methylacetate, n-propyl acetate, i-propyl acetate, n-butyl acetate, i-butylacetate, di(propylene glycol) methyl ether acetate, phenyl acetate,ethylene glycol diacetate, propylene glycol diacetate, and glyceryltriacetate.

In another aspect, compound (II) is an amide of formula (IIB):CH₃CO—NR¹⁰R¹¹  (IIB)wherein:

R¹⁰ and R¹¹ are independently selected from: H, a C₁₋₁₀ alkyl group, aC₁₋₁₀ substituted alkyl group, a C₆₋₁₈ aromatic ring group, and a C₆₋₁₈substituted aromatic ring group;

alternatively, R¹⁰ and R¹¹ are linked to each other to form a 5-6membered ring that optionally contains a hetero atom selected from:nitrogen, oxygen, and sulfur.

Examples of amides include CH₃CONH-phenyl (R¹⁰=H, R¹¹=phenyl),CH₃CONHCH₂CH₃ (R¹⁰=H, R¹¹=ethyl). Examples of NR¹⁰R¹¹ being a ringinclude morpholine and piperidine.

In another aspect, the glycol ether group of R⁶, R⁷, or R⁸ is selectedfrom a compound of formula (IIC) and (IID):—R¹²—O—R¹³  (IIC)—R¹²—O—R¹⁴—O—R¹³  (IID)wherein:

R¹² and R¹³ are independently selected from: a C₁₋₁₀ alkyl group; and,

R¹⁴ is a C₁₋₁₀ alkylene group.

In another aspect, R¹² and R¹³ are independently selected from: a C₁₋₆alkyl group and R¹⁴ is a C₁₋₆ alkylene group.

In another aspect, R¹²=CH₃, R¹³=CH₃, and R¹⁴=—CH₂—.

The catalyst of formula (III) is suitable for the reduction of an esteror an amide to the corresponding alcohol or amine.

In another aspect, transition metal “M” is selected from: Fe, Co, Ni,Mn, Pd, Pt, Rh, Ru, Os and Ir.

In another aspect, the transition metal is selected from: Pd, Pt, Rh, Ruand Ir.

In another aspect, the transition metal is Ru.

Ligand “L” is any ligand suitable for the reduction of esters or amides.In another aspect, the ligand is selected from: a monodentate ligand anda polydentate ligand. Examples of monodentate ligands include phosphine(e.g., triphenylphosphine), carbon monoxide, an olefin, water,acetonitrile, dimethylsulfoxide. Examples of polydentate ligands includean olefin (e.g., cyclooctadiene), an amino phosphine (e.g.,2-(diphenylphosphanyl)ethan-1-amine andbis(2-(diphenylphosphanyl)ethyl)amine), a bypiridine (e.g.,4,4′-dimethoxy-2,2′-bipyridine).

When “a” is from 2 to 5, each of the ligands may be the same ordifferent.

In another aspect, ligand L is carbon monoxide (CO).

In another aspect, counterion “X” is selected from:pentamethylcyclopentadienyl, chloride, bromide, iodide, hydride,triflate, and BH₄.

When “b” is from 2 to 5, each of the counterions may be the same ordifferent.

In another aspect, one of the counterions X is hydride.

In another aspect, M, L, and X are as follows:

M is Ru;

L is selected from phosphine, carbon monoxide, olefin, water,acetonitrile, dimethylsulfoxide, amino phosphine, and bypiridine; and,

X is selected from pentamethylcyclopentadienyl, chloride, bromide,iodide, hydride, triflate, and BH₄.

In another aspect, the catalyst is a ruthenium complex of generalformula (IV):

wherein:

each R¹⁵ is independently selected from: a hydrogen atom, a C₁₋₁₀ alkylgroup, a substituted C₁₋₁₀ alkyl group, a C₆₋₁₈ aromatic ring group, anda substituted C₆₋₁₈ aromatic ring group;

each Ar is independently selected from a C₆₋₁₈ aromatic ring group and asubstituted C₆₋₁₈ aromatic ring group; and,

each n is independently selected from an integer of 1 or 2.

The ruthenium catalysts of formula (IV) are known (see U.S. Pat. No.8,003,838, US2013/0303774, and US2016/0039853, which are incorporatedherein by reference).

In another aspect, the ligand L is a monodentate ligand.

In another aspect, L is selected from: phosphine (e.g.,triphenylphosphine), carbon monoxide, olefin, water, acetonitrile anddimethylsulfoxide.

In another aspect, L is carbon monoxide.

In another aspect, X is selected from: pentamethylcyclopentadienyl,chloride, bromide, iodide, hydride, triflate, and BH₄.

In another aspect, one of X is hydride.

In another aspect, in formula (IV) two vicinal R¹⁵ (except hydrogenatoms) may form a cyclic structure by covalent bond of carbon atomsthrough or without a nitrogen atom, an oxygen atom or a sulfur atom.

In another aspect, in formula (IV), each Ar is phenyl.

In another aspect, n is 1 (each P is bound to the N in the Ru complexvia a 2 carbon linker).

In another aspect, n is 2 (each P is bound to the N in the Ru complexvia a 3 carbon linker).

In another aspect, n=1 and all R¹²=hydrogen.

In another aspect, L is carbon monoxide and one of X is hydride.

In another aspect, the catalyst is a Ru complex of formula (V) (which iscommercially available asRu-MACHO®)({Bis[2-(diphenylphosphino)ethyl]amine}carboynlchlorohydridoruthenium(II)):

wherein Ph=phenyl.

In another aspect, the catalyst is a Ru complex of formula (VI) (whichis commercially available asRu-MACHO®-BH)(Carbonylhydrido(tetrahydroborato)[bis(2-diphenylphosphinoethyl)amino]ruthenium(II)):

wherein Ph=phenyl.

In another aspect, the catalyst is a Ru complex of formula (VII)(Ru-Firmenich as described in Angew. Chem. Int. Ed. 2007, 46,7473-7476);

wherein Ph=phenyl.

In another aspect, the catalyst is a Ru complex of formula (VIII)(Cp₃Ir(BiPy)(OTf)₂ as described in JACS, 2013, 135, 16022));

wherein Cp=cyclopentadienyl, BiPy=bipyridine, and OTf=triflate.

In another aspect, the catalyst is the compound of formula (VI) and thereaction is performed in the absence of a base. This results in a highselectivity for the D incorporation in R⁴-R⁵ over R¹-R³.

In another aspect, when the catalyst is the compound of formula (VI),then compound (II) is selected from: methyl acetate, n-propyl acetate,i-propyl acetate, n-butyl acetate, i-butyl acetate, and glyceryltriacetate.

In another aspect, the reaction is performed in the absence of base.

In another aspect, the reaction is performed in the presence of base.

Examples of the base include

-   -   a. alkali metal hydrogen carbonates (e.g., LiHCO₃, NaHCO₃, and        KHCO₃); alkali metal carbonates (e.g., Li₂CO₃, Na₂CO₃, and        K₂CO₃);    -   b. alkali metal hydroxides (e.g., LiOH, NaOH, and KOH);    -   c. tetraalkyl ammonium hydroxides (e.g., N(CH₃)₄OH,        N(CH₂CH₃)₄OH, N(CH₂CH₂CH₃)₄OH, and N(CH₂CH₂CH₂CH₃)₄OH);    -   d. alkali metal alkoxides (e.g, LiOCH₃, NaOCH₃, KOCH₃,        LiOCH₂CH₃, NaOCH₂CH₃, KOCH₂CH₃, LiOCH(CH₃)₂, NaOCH(CH₃)₂,        KOCH(CH₃)₂, LiOC(CH₃)₄, NaOC(CH₃)₄, KOC(CH₃)₄;    -   e. organic bases (e.g., triethylamine, diisopropylethylamine,        4-dimethylaminopyridine, and        1,8-diazabicyclo[5.4.0]undec-7-ene);    -   f. alkali metal bis(trialkylsilyl)amides (e.g., lithium        bis(trialkylsilyl)amide, sodium bis(trialkylsilyl)amide, and        potassium bis(trialkylsilyl)amide); and    -   g. alkali metal borohydrides (e.g., LiBH₄, NaBH₄, and KBH₄).

In another aspect, the reaction is performed in the presence of analkali metal alkoxide. Examples of alkali metal alkoxides includeLiOCH₃, NaOCH₃, and KOCH₃.

In another aspect, the reaction is performed in the presence of analkali metal borohydride. Examples of alkali metal borohydrides includeLiBH₄, NaBH₄, and KBH₄.

In another aspect, the amount of the base is 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, to 10 mol % with respectto compound (II).

In another aspect, the catalyst is compound (V) (Ru-MACHO®) and thereaction is performed in the presence of a base. Examples of the baseinclude NaBH₄ and KOCH₃. In another example, the base is NaBH₄. Thecombination of Ru-MACHO® and NaBH₄ results in a high selectivity for theD incorporation in R⁴-R⁵ over R¹-R³.

In another aspect, the catalyst is compound (VI) (Ru-MACHO®-BH) and thereaction is performed in the presence of a base.

In another aspect, the catalyst is compound (VI) (Ru-MACHO®-BH) and thereaction is performed in the absence of a base. This results in a highselectivity for the D incorporation in R⁴-R⁵ over R¹-R³.

In another aspect, the catalyst is compound (VII) (Ru-Firmenich) and thereaction is performed in the presence of a base. Examples of the baseinclude KOCH₃ and NaBH₄. The use of KOCH₃ results in a higher conversionbut low selectivity. The use of NaBH₄ results in a lower conversion buthigh selectivity.

In another aspect, the catalyst is compound (VIII) (Cp₃Ir(BiPy)(OTf)₂)and the reaction is performed in the presence of a base

In another aspect, the catalyst is compound (VIII) (Cp₃Ir(BiPy)(OTf)₂)and the reaction is performed in the absence of a base.

In another aspect, the reaction is performed under neat conditionswithout the use of a solvent.

In another aspect, the reaction is performed in the presence of anorganic solvent.

Examples of the organic solvent include:

-   -   a. aliphatic hydrocarbon solvents (e.g., n-hexane and        n-heptane);    -   b. aromatic hydrocarbon solvents (e.g., toluene and xylene);    -   c. halogenated solvents (e.g., methylene chloride and        1,2-dichloroethane);    -   d. ether solvents (e.g., diethyl ether, 1,2-dimethoxyethane,        1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran,        tert-butyl methyl ether, diisopropyl ether, diethylene glycol        dimethyl ether, and anisole);    -   e. alcohol solvents (e.g., methanol, ethanol, n-propanol,        isopropanol, n-butanol, tert-butanol, n-pentanol, n-hexanol, and        cyclohexanol);    -   f. amide solvents (e.g., N,N-dimethylformamide and        1,3-dimethyl-2-imidazolidinone);    -   g. nitrile solvents (e.g., acetonitrile and propionitrile); and    -   h. dimethyl sulfoxide.

The organic solvents can be used solely or in combination of two or morethereof.

In another aspect, the solvent is selected from: tetrahydrofuran,methanol, and 1,4-dioxane.

The organic solvent may also be a deuterated organic solvent, i.e. anorganic solvent listed above wherein at least one H is replaced by D.Examples include CD₃OD (perdeutero-methanol) and d₈-tetrahydrofuran(d₈-THF)(perdeutero-THF).

In another aspect, the amount of solvent is 0.01, 0.02, 0.03, 0.04,0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, to 10 L per mole of compound (II).

In another aspect, the reaction is performed with a D₂ pressure of 0.1,0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, to 20 MPa. Examples of the pressureinclude from 1, 2, 3, 4 to 5 MPa of D₂.

In another aspect, the reaction temperature is at most 200° C. Examplesof the reaction temperature include from 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, to 125° C. Furtherexamples include from 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95 to 100° C. Other examples include from 70, 71, 72, 73, 74,75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, to 90° C.(e.g., 70-90° C.).

In another aspect, the reaction is performed at a period of 0.5, 1, 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95to 100 hours. Examples of the time the reaction is performed includefrom 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34,36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70to 72 hours.

In another aspect, compound (I) can be separated from the reactionproduct by any ordinary post treatment operation for organic synthesis.Further, the crude product can be purified to a high purity, as needed,by standard methods including, activated carbon treatment, fractionaldistillation, recrystallization, and column chromatography. It can beconvenient to directly subject the completed reaction solution to adistillation recovery operation.

In the case where the reaction is performed in the presence of a base,the target compound of relatively high acidity tends to form a salt orcomplex with the base used and remain in the distillation residue duringdistillation recovery operation. In such a case, the target compound canbe obtained with high yield by neutralizing the reaction completedsolution with an organic acid (e.g., formic acid, acetic acid, citricacid, oxalic acid, benzoic acid, methanesulfonic acid orparatoluenesulfonic acid) or an inorganic acid (e.g., HCl, HBr, HNO₃,H₂SO₄) in advance, and then, subjecting the neutralized reactioncompleted solution to a distillation recovery operation (includingrecovery by washing the distillation residue with an organic solventsuch as diisopropyl ether).

It is noted that the invention relates to all possible combinations offeatures described herein. It will therefore be appreciated that allcombinations of features relating to the composition according to theinvention; all combinations of features relating to the processaccording to the invention and all combinations of features relating tothe composition according to the invention and features relating to theprocess according to the invention are described herein.

It should be understood that a description on a product/compositioncomprising certain components also discloses a product/compositionconsisting of these components. The product/composition consisting ofthese components may be advantageous in that it offers a simpler, moreeconomical process for the preparation of the product/composition.Similarly, it should be understood that a description on a processcomprising certain steps also discloses a process consisting of thesesteps. The process consisting of these steps may be advantageous in thatit offers a simpler, more economical process.

Definitions

The examples provided in the definitions present in this application arenon-inclusive unless otherwise stated. They include but are not limitedto the recited examples.

When values are mentioned for a lower limit and an upper limit for aparameter, ranges made by the combinations of the values of the lowerlimit and the values of the upper limit are also understood to bedisclosed.

“Alkyl” includes the specified number of carbon atoms in a linear,branched, and cyclic (when the alkyl group has 3 or more carbons)configuration. Alkyl includes a lower alkyl groups (C₁, C₂, C₃, C₄, C₅,and C₆ or 1-6 carbon atoms). Alkyl also includes higher alkyl groups(>C₆ or 7 or more carbon atoms).

When an “ene” terminates a group it indicates the group is attached totwo other groups. For example, methylene refers to a —CH₂-moiety.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, andC₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂₋₆ alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynyl groups.

“Substituted alkyl” is an alkyl group where one or more of the hydrogenatoms have been replaced with another chemical group (a substituent).Substituents include: halo, OH, OR (where R is a lower alkyl group),CF₃, OCF₃, NH₂, NHR (where R is a lower alkyl group), NR^(x)R^(y) (whereR^(x) and R^(y) are independently lower alkyl groups), CO₂H, CO₂R (whereR is a lower alkyl group), C(O)NH₂, C(O)NHR (where R is a lower alkylgroup), C(O)NR^(x)R^(y) (where R^(x) and R^(y) are independently loweralkyl groups), CN, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₂ aromatic ringgroup, substituted C₆₋₁₂ aromatic ring group, 5-12 membered aromaticheterocyclic group, and substituted 5-12 membered aromatic heterocyclicgroup.

Examples of the aromatic ring group are aromatic hydrocarbon groups astypified by phenyl, naphthyl and anthryl.

Examples of the aromatic heterocyclic group are aromatic hydrocarbongroups containing hetero atoms e.g. as nitrogen, oxygen or sulfur astypified by pyrrolyl (including nitrogen-protected form), pyridyl,furyl, thienyl, indolyl (including nitrogen-protected form), quinolyl,benzofuryl and benzothienyl.

“Substituted aromatic ring group” or “substituted aromatic heterocyclicring group” refers to an aromatic/aromatic heterocyclic ring group whereat least one of the hydrogen atoms has been replaced with anotherchemical group. Examples of such other chemical groups include: halo,OH, OCH₃, CF₃, OCF₃, NH₂, NHR (where R is a lower alkyl group),NR^(x)R^(y) (where R^(x) and R^(y) are independently lower alkylgroups), CO₂H, CO₂R (where R is a lower alkyl group), C(O)NH₂, C(O)NHR(where R is a lower alkyl group), C(O)NR^(x)R^(y) (where R^(x) and R^(y)are independently lower alkyl groups), CN, lower alkyl, aryl, andheteroaryl.

“Halo” refers to Cl, F, Br, or I.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

The structures of the compound (II) tested are as follows:

The structures of the catalysts used are shown below.

Experiment Set 1

In a glovebox, under N₂ atmosphere, the catalyst (and base whenrequired) was placed inside 5 mL vials under N₂ atmosphere. The solventwhen used was added followed by the substrate (compound (II)). The vialwas placed inside an autoclave and purged with D₂. The pressure of D₂was increased to 50 bar and the temperature was increased to 70° C.while stirring at 500 rpm with a magnetic stirred. After 16 h, thereaction mixture was cooled. After purging with N₂, the autoclave wasopened and the reaction mixture was analyzed by ¹H NMR to determine theconversion and D incorporation.

The reaction conditions were as follows: 50 bar D₂, Substrate=15-20 wt%, ratio of Substrate/Catalyst=1000, Base=5 mol % relative to substratewhen present, 70° C., 16 h.

The experiments were performed using methyl acetate with variouscatalysts. Results are shown in Table 1.

TABLE 1 D D inc. inc. at at Catalyst Conv CH₂ CH₃ Exp Id mmol SubstrateSolvent (%) (%) (%) 1 Ru- 0.027 Me neat >99 >99 <1 MACHO- Acetate BH 2Ru- 0.0027 Me d₈-THF >99 >99.2 <1 MACHO- Acetate (1.4 mL) BH 3 Ru-0.0027 Me d₄-MeOH >99 99 3 MACHO- Acetate (1.4 mL) BH 4 Ru- 0.0027 Med₈-THF >99 95 68 MACHO Acetate (1.7 mL) 5 Ru- 0.0027 Me d₈-THF >99 90 92Firmenich Acetate (1.7 mL)For experiments 4 and 5, KOMe (potassium methoxide) was added (50eq/Ru).

The reaction of the acetate with D₂ results in a deuterated ethanol anda further (side-product) alcohol. The type of the further alcoholdepends on the type of the acetate, e.g. when the acetate is methylacetate, the further alcohol is methanol. The abundance of D in the CH₂position and the CH₃ position was determined by subjecting the resultingmixture to ¹H NMR. The abundance of D in the CH₂ position was determinedby the amount of the residual H in the CH₂ position. The “residual H atthe CH₂ position” was determined by the normalized ratio of area of theCH₂ signal in the ethanol produced divided by the area of the signal ofthe further alcohol. The complement to 100 of this quantity equals tothe abundance of D in the CH₂ position. The abundance of D in the CH₃position was determined in a similar manner.

In Exp 1, Ru-MACHO-BH gives full conversion of methyl acetate to adeuterated ethanol with a deuterium incorporation over 99% in the CH₂position and no significant deuterium incorporation in the CH₃ position.The reaction was conducted without any solvent. Similar results wereobtained when the reaction is done in THF or MeOH as solvent (Exp 2 and3).

Ru-MACHO (Exp 4) or Ru-Firmenich (Exp 5) need to be activated by astrong base such as KOMe. In this case, a good conversion of Me acetatewas observed but a significant D incorporation at CH₃ was also observed.

Exp 1 was repeated except that the pressure was 5 bar D₂ instead of 50bar D₂. The conversion was 87% with 99% D incorporation at CH₂ position.

Experiment Set 2

The experiments were performed in the same way as in Experiment Set 1using various substrates with Ru-MACHO-BH, except experiment 11 whichuses Ru-MACHO. Results are shown in Table 2.

TABLE 2 D D inc. inc. at at Catalyst Conv CH₂ CH₃ Exp Id mmol SubstrateSolvent (%) (%) (%) 6 Ru- 0.027 n-Pr Acetate neat >99 77 low Macho- ifBH any 7 Ru- 0.027 n-Bu Acetate neat >99 77 low Macho- if BH any 8 Ru-0.027 i-Pr Acetate neat 75 92 low Macho- if BH any 9 Ru- 0.027 i-BuAcetate neat 100 77 low Macho- if BH any 10 Ru- 0.011 Glyceryl neat 6799 Macho- triacetate BH 11 Ru- 0.0017 tBu Acetate d₈-THF 32 n.d. n.d.Macho (1.5 mL)

When Ru-Macho-BH was used as the catalyst, methyl acetate led to thehighest selectivity for the D-incorporation at CH₂. The other acetateswere also tested with Ru-Macho-BH without any solvent (Exp 6-10). Goodconversions were obtained in all cases. However, a lower D incorporationat CH₂ position was obtained by the other acetates compared with methylacetate (Exp 1). This may be due to H/D exchange between the alcoholsformed. This H/D exchange may not occur in the case of MeOH producedwhen the acetate is methyl acetate.

Further, deuterated ethanol was obtained from tBu acetate using Ru-Machoas the catalyst although at a lower conversion (Ex 11).

Experiment Set 3

The experiments were performed in the same way as in Experiment set 1using methyl acetate with various catalysts. Results are shown in Table3.

The reaction conditions were as follows: neat, P(D₂)=50 bar, T=90° C.,time=16 h.

TABLE 3 D D inc. inc. at at mmol tot V Conv CH₂ CH₃ Exp Catalyst CatSubs. Mmol (mL) S:Cat (%) (%) (%) 12 Ru-Macho- 0.011 Me 13.8 1.11285 >99 97 low BH Acetate if any 13 Ru-Macho + 0.0155 Me 6.3 0.5406 >99 87 low NaBH₄ Acetate if (15 eq/Ru) any 14 Ru-Firmenich + 0.007Me 6.3 0.5 900 36 >99 20 NaBH₄ Acetate (7 eq/Ru) 15 Cp*Ir(BiPy) 0.023 Me6.3 0.5 274 41 >99 22 (OTf)₂ Acetate

In Exp 13, the in-situ activation of Ru-Macho with NaBH₄ also gives anactive catalyst leading to a good D incorporation. The selectivitytowards D incorporation at the CH₂ position is higher than when KOMe isused as the base. The Firmenich catalyst activated in-situ with NaBH₄led to an excellent D incorporation at CH₂ position but also with some Dincorporation at CH₃ position. The conversion is lower than when KOMe isused as the base. In Exp 15, a catalyst based on Ir instead of Ru wasalso successful at producing the desired deuterated ethanol.

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

What is claimed is:
 1. A process for the preparation of a deuteratedethanol of the formula (I)CR¹R²R³CR⁴R⁵OD  (I) comprising: reacting compound (II) with D₂ in thepresence of a catalyst of formula (IV):

wherein: R¹-R⁵ are independently H or D, provided that the abundance ofD in R⁴ and R⁵ is at least 70%; each R¹⁵ is independently selected from:a hydrogen atom, a C₁₋₁₀ alkyl group, a substituted C₁₋₁₀ alkyl group, aC₆₋₁₈ aromatic ring group, and a substituted C₆₋₁₈ aromatic ring group;each Ar is independently selected from a C₆₋₁₈ aromatic ring group and asubstituted C₆₋₁₈ aromatic ring group; each n is independently selectedfrom an integer of 1 or 2; compound (II) is an acetate; L is a ligand;and, X is a counterion.
 2. The process of claim 1, wherein the abundanceof D in R¹-R³ is at most 50%.
 3. The process of claim 1, wherein theprocess has a conversion to compound (I) of at least 90%.
 4. The processof claim 1, wherein compound (II) is an acetate selected from: methylacetate, n-propyl acetate, i-propyl acetate, n-butyl acetate, i-butylacetate, di(propylene glycol) methyl ether acetate, phenyl acetate,ethylene glycol diacetate, propylene glycol diacetate, and glyceryltriacetate.
 5. The process of claim 1, wherein compound (II) is anacetate represented by the formula CH₃COOR⁶, wherein an alcohol madefrom R⁶ represented by R⁶OH is a primary or a secondary alcohol.
 6. Theprocess of claim 1, wherein compound (II) is methyl acetate.
 7. Theprocess of claim 1, wherein the catalyst is selected from catalysts offormula (V) and (VI):


8. The process of claim 7, wherein the catalyst is of formula (V). 9.The process of claim 8, wherein compound (II) is selected from: methylacetate, n-propyl acetate, i-propyl acetate, n-butyl acetate, i-butylacetate, and glyceryl triacetate.
 10. The process of claim 8, whereincompound (II) is methyl acetate.
 11. The process of claim 8, wherein thereaction is performed in the presence of a base.
 12. The process ofclaim 11, wherein the base is NaBH₄.
 13. The process of claim 12,wherein compound (II) is selected from: methyl acetate, n-propylacetate, i-propyl acetate, n-butyl acetate, i-butyl acetate, andglyceryl triacetate.
 14. The process of claim 12, wherein compound (II)is methyl acetate.
 15. The process of claim 7, wherein the catalyst isof formula (VI).
 16. The process of claim 15, wherein compound (II) isselected from: methyl acetate, n-propyl acetate, i-propyl acetate,n-butyl acetate, i-butyl acetate, and glyceryl triacetate.
 17. Theprocess of claim 15, wherein compound (II) is methyl acetate.
 18. Theprocess of claim 1, wherein the reaction is performed under neatconditions without the use of a solvent.
 19. The process of claim 1,wherein the reaction is performed in the presence of a solvent selectedfrom THF, methanol, d₈-THF, and d₄-methanol.
 20. The process of claim 1,wherein the reaction is performed with a D₂ pressure of 0.1 to 20 MPaand a temperature of 25 to 125° C.
 21. The process of claim 1, whereinthe reaction is performed at a temperature of 70 to 90° C.
 22. Theprocess of claim 1, wherein the abundance of D in R⁴ and R⁵ is at least80%.
 23. The process of claim 1, wherein the abundance of D in R⁴ and R⁵is at least 90%.
 24. The process of claim 1, wherein the abundance of Din R⁴ and R⁵ is at least 90% and the abundance of D in R¹-R³ is at most5%.
 25. The process of claim 1, wherein the abundance of D in R⁴ and R⁵is at least 95% and the abundance of D in R¹-R³ is at most 1%.
 26. Theprocess of claim 1, wherein the abundance of D in R⁴ and R⁵ is at least99% and the abundance of D in R¹-R³ is at most 1%.